Study of Low-Intensity Focused Ultrasound in Combination With Immunotherapy in Newly Diagnosed Unmethylated Glioblastoma

Official title

Phase I Clinical Trial of Anti-CD3 × Anti-EGFR Bispecific-armed T Cells (EGFR BATs) and Low-Intensity Focused Ultrasound (LIFU) Blood-brain Barrier Opening in Patients With MGMT Unmethylated Glioblastoma (GBM)

Overview

This is a phase 1 study for patients with newly diagnosed MGMT unmethylated IDH wild-type glioblastoma utilizing autologous activated T-cells armed with bispecific antibody (EGFR-BATs) that recognize the tumor. The investigators hypothesized that the combination of infusions of EGFR BATs and low-intensity focused ultrasound would induce blood-brain barrier opening and increase the permeability of the adoptive immunotherapy. The investigators will radiolabel the EGFR BATs with 89Zr-oxine for subsequent PET imaging to determine the trafficking and uptake of this approach. There is a concern that several infusions of EGFR BATs before BBB opening could change the immune tumor microenvironment that would not allow a permissive BBB after LIFU. Therefore, Arm A will have two LIFU with BBB opening after the 4th and the 8th infusion, and Arm B will have three LIFU with BBB opening after the 1st, 4th, and 8th infusions. This study will determine the safety and feasibility of the combination of low-intensity focused ultrasound (LIFU) with microbubbles BBB opening and EGFR BATs and the access of the adoptive cell immunotherapy to the tumor microenvironment to inform future studies.

Interventions

• Drug anti-EGFR bispecific-armed T cells
  IN PROGRESS
• Device Low-Intensity Focused Ultrasound
  Low-Intensity Focused Ultrasound will be used to open the blood-brain barrier

Primary outcome measures

• The safety of this treatment will be evaluated through the number of participants experiencing Grade ≥3 dose-limiting toxicities (DLTs). [Time frame: 8 weeks]
• The feasibility of this treatment will be determined by the proportion of participants achieving ≥75% of the recommended EGFR BATs dose [Time frame: 8 weeks]
• Incidence and severity of treatment-emergent adverse events (AEs) based on physical examination, vital signs, laboratory parameters, serum chemistry and hematology [Time frame: 8 weeks]
• Brain uptake of 89Zr-oxine-labeled EGFR BATs measured by PET standardized uptake values (SUV) with and without LIFU BBB opening [Time frame: 8 weeks]

Secondary outcome measures (12)

• Change from baseline in peripheral immune response markers (CTL cytotoxicity) [Time frame: 8 weeks]
• Change from baseline in peripheral immune response markers (IFN-γ ELISpot Counts) [Time frame: 8 weeks]
• Change from baseline in peripheral immune response markers (Th1/Th2 serum cytokine concentrations) [Time frame: 8 weeks]
• PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment after infusions and Low Intensity Focused Ultrasound (LIFU). [Time frame: 8 weeks]
• PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment with versus without Low Intensity Focused Ultrasound (LIFU). [Time frame: 8 weeks]
• Quantitative levels of circulating tumor DNA (ctDNA) [Time frame: 8 weeks]
• Quantitative levels of antibodies against tumor-associated antigens (IgG anti-EGFR and IgG anti-HER2) [Time frame: 8 weeks]
• Progression-free survival (PFS) measured using modified Response Assessment in Neuro-Oncology (RANO) criteria. [Time frame: From date of surgery to date of first documented progression, assessed up to 104 weeks.]
• Overall survival (OS) [Time frame: From date of surgery to date of documented death, assessed up to 104 weeks.]
• Correlation between immune response measures and clinical outcomes [Time frame: From baseline until 1-year post-treatment completion]
• Objective response rate (ORR) per modified Response Assessment in Neuro-Oncology (RANO) criteria [Time frame: From baseline until 1-year post-treatment completion]
• Incidence and severity of adverse events (AEs) and laboratory abnormalities [Time frame: From baseline through 30-days post-treatment completion]

Eligibility criteria

Inclusion criteria

• Newly diagnosed supratentorial glioblastoma or gliosarcoma IDH wildtype and MGMT unmethylated that express EGFR (score ≥ 1 by IHC)) and confirmed by UVA pathology review.
• Age ≥ 18 and ≤ 70 years at the time of signing informed consent.
• Karnofsky Performance Status (KPS) ≥ 70.
• Be willing and able to provide written informed consent for the trial.
• Females of childbearing potential, and males, must be willing to use an effective method of contraception.
• Maximal surgical debulking of the tumor was performed where residual contrast enhancement is 2 cm3 or less on immediate post-operative MRI. Intraoperative post-resection MRI is acceptable.
• Able to communicate during the LIFU BBB opening procedure.
• BBB opening target(s) must lie in non-eloquent area(s).
• The brain tumor to be treated must be in the treatment envelope of the NaviFUS system with a minimum distance of 30 mm from the inner skull table.
• Females of childbearing potential should have a negative serum pregnancy test. Males who are partners of females of childbearing potential must agree to use an acceptable method of contraception throughout the study and for 1 month following completion of the EGFR BATs infusions.
• Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days before leukapheresis.

Exclusion criteria

• Patients with a diagnosis of another malignancy within 2 years of being on-study. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or any type of in situ cancer. Patients must not be on any treatment for another malignancy.
• Patients undergoing only biopsy (partial resection or greater is required).
• Patients with cerebellar or brainstem tumors.
• Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
• Patients with extracranial metastases.
• Patients with evidence of acute intracranial hemorrhage.
• Known hypersensitivity to cetuximab or another EGFR antibody.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to Lumason® ultrasound contrast agent.
• Alpha 1,3 Galactose IgE ("alpha gal") test result outside of the reference range (indicating likely hypersensitivity to cetuximab).
• Patients with claustrophobia.
• Clips, shunts, or other non-MRI compatible metallic implanted objects in the skull or the brain.
• Evidence of active bleeding or bleeding diathesis.
• Unable to discontinue use of anticoagulant therapy as per local standard.
• Scalp atrophy or scars in the expected location of the ultrasound transducer.
• Cardiac Status: Patients will be ineligible for treatment on this protocol if (before protocol entry):

• There is a history of a recent (within one year) myocardial infarction or stroke.
• There is a current or prior history of angina/coronary symptoms requiring medications and/or a history of depressed left ventricular function (LVEF < 45%).
• Patient has a pacemaker.
• There is clinical evidence of congestive heart failure requiring medical management.
• Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
• Has received a live vaccine within 30 days of leukapheresis.
• Has received any treatment for GBM besides surgery.
• Females must not be pregnant or breastfeeding.
• Ongoing immunosuppressive therapy except for corticosteroids
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• A patient may be excluded if, in the opinion of the treating investigator, the patient is not capable of being compliant.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Virginia — Charlottesville

Publications

• Fadul CE, Thakur A, Kim J, Kassay-McAllister J, Schalk D, Lopes MB, Donahue J, Purow B, Dillon P, Le T, Schiff D, Liu Q, Lum LG. Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide. J Neurooncol. 2024 Jan;166(2):321-330. doi: 10.1007/s11060-024-04564-y. Epub 2024 Jan 23. PMID 38263486

Identifiers

NCT: NCT07343986 · HSR231550

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗